The purpose of this project is to identify, that is, "clone," the RP10 gene which causes autosomal dominant retinitis pigmentosa (adRP). In preliminary research we localized the RP10 gene to human chromosome 7q31 by linkage mapping in 4 large, unrelated adRP families. The region containing the RP10 gene, flanked by markers D7S2471 and RP-STR12, is 3.3 mbp in length. By combining the public (GenBank) and private (Celera) human genome sequences, we have assembled 99% of the complete sequence in this region. Likewise, the Celera database contains 99% of the syntenic mouse sequence. By computational analysis and laboratory methods we have identified 38 independent, expressed sequences in the region, 10 of which are retinal-expressed and, thus, possible disease-gene candidates. We propose to complete the task of cloning the RP10 gene by building on these findings and resources. [unreadable] [unreadable] Proposed aims are 1) to reduce the RP10 linkage region, 2) to complete the physical and transcriptional maps of the region and 3) to test candidate genes in RP10 families. Methods for Aim 1 include enhanced linkage analysis and SNP haplotype testing to refine breakpoints; and production of haploid cell lines from patients to facilitate testing. Methods for Aim 2 include further computational analyses, comparing mouse and human genomes; and prioritization of candidate genes based on transcript profiles and function. Methods for Aim 3 include detection of retinal and photoreceptor-expressed genes in the region using knockout mice; candidate gene screening; and confirmation of positive results in unrelated adRP patients. These studies will be done in collaboration with the South African National Bioinformatics lnstitute, and the Ocular Genetics Unit, Trinity College, Dublin. [unreadable] [unreadable] Mutations in the RP10 gene may cause at least 10% of adRP which, in turn, affects thousands of Americans. Identification of the RP10 gene will provide direct benefits to affected individuals through diagnosis and counseling. Also, it is a necessary first step in designing gene-specific therapies and identifying modifying factors. More broadly, identification of genes causing retinitis pigmentosa has revealed new functional pathways in the retina, thus cloning the RP10 gene will likely contribute to a better understanding of normal visual processes.